Preparation of isocinchomeronic acid



Patented Oct. 27, 1953 UNITED STATES ATENT OFFICE PREPARATION OF ISOCINCHOMERONIC ACID Ware

No Drawing. Application February 27, 1951, Serial No. 213,057

4 Claims.

This invention relates to a new and improved,

process for the manufacture of metal salts of isocinchomeronic acid, and of the free acid itself, and more particularly to such a process giving increased yields and improved quality of product.

This is a continuation-in-part of my co-pending application, Serial No. 4,699, filed January 2'7, 1948,-now abandoned.

It is well known that the controlled oxidation of various alkylpyridines, using suitable oxidizing agents, brings about the formation of certain amounts of the corresponding carboxylic acids. Oxidations have been effected by means of chromates, peroxides, and potassium permanganate, for example, and nitric acid and nitrogen oxides have likewise been proposed. Many of the carboxylic acids so produced are important chemical products, either per se or as intermediates in the preparation of other compounds. Isocinchomeronic acid, for example, is such a potentially important chemical intermediate. Its use has been suggested in dyeing, for example, particularly for the manufacture of vat dyes which will not harm the fiber. It may also be decarboxylated to nicotinic acid and for this purpose high purity is desirable. The salts of isocinchomeronic acid are likewise useful chemical materials. Isocinchomeronic acid may be prepared, for example, by the oxidation of 2,5-dialkylpyridines by means of concentrated nitric acid at elevated temperature and under pressure greater than atmospheric, as in U. S. Patent 2,524,957. In accordance with this process, however, much of the di carboxylic acid remains in solution in the mother liquor and must be recovered therefrom by subsequent treatment, such as by precipitation of the copper salt. This subsequent treatment entails considerable consumption of time and loss in potential yield, and the product obtained is not of the highest quality desired.

An object of the present invention is an improved process for the preparation of isocinchomeronic acid by the nitric acid oxidation of 2,5-dialkylpyridines. A further object is such a process for the production first of metallic salts of isocinchomeronic acid. A still further object is an improved process for the preparation of metallic salts of isocinchomeronic acid and subsequently of the free acid by the oxidation of a 2,5-dialkylpyridine with the employment of nitric acid. A further object is such a method in which the starting material is 5-ethyl-2-methylpyridine and in which excellent yields are obtained and a product of superior quality. Additional objects 2 will be disclosed as the invention is described more at length hereinafter.

I have found that the foregoing objects are accomplished when I employ a procedure for the oxidation process which comprises heating at an elevated temperature and under superatmospheric pressure a 2,5-dialkylpyridine and concentrated nitric acid, and carrying out the reaction in the presence of a metallic salt of an inorganic acid. A metal salt of isocinchomeronic acid results therefrom and the free acid may be obtained by heating the separated metal salt with an excess of alkali, filtering to recover the metal oxide, and acidifying the filtrate with sulfuric or other strong inorganic acid to a pH at which substantially all of the carboxylic acid is present as free acid, which may then be separated. Copper nitrate has been found to be very advantageous for use in the process and this may be introduced into the reaction as such in the solid or dissolved state, or copper oxide may be added, which is converted to the nitrate by reaction with the nitric acid present. The process will be shown more clearly by the following examples, which are not to be taken as limiting in any way.

Example 1 Three grams of 5-ethyl-2-methylpyridine was introduced with cooling beneath the surface of 30 grams of nitric acid, and 6 grams of cupric nitrate, Cl1(NO'3)2'3H20, was added to the solution. This solution was placed in a heavy-walled glass tube, having an internal volume of 900 cc. The tube was sealed, placed in a steel jacket, and heated at 180 C. for 45 min. At the end of the reaction, the tube was cooled and opened, and the contents removed. Copper diisocinchomeronate, having the formula (CvH4O4N) zCu, in the form of large blue crystals, was filtered off, washed, and dried at 110 C. The yield of the copper salt from the 5-ethyl-2-methylpyridine amounted to 94.51%. In this example, the copper present constituted an excess of over that required to form the salt, and the net ratio of nitric acid to 5-ethyl-2-methylpyridine by weight was 6.

The above copper diisocinchomeronate was then digested with an excess of sodium hydroxide in dilute aqueous solution. This caused the precipitation of the copper oxide, which was separated by filtration. Sulfuric acid was then added to the filtrate to give a pH value of 2.5, whereupon the free isocinchomeronic acid precipitated and was washed and dried. A yield of 88.2% Of the free acid was obtained, so that the over-all yield from 5-ethy1-2-methylpyridine was 83.3%.

9: a An excellent-quality of both the copper salt and free isocinchomeronic acid was obtained.

The present example describes a starting run, in which fresh copper nitrate was used. In succeeding runs,,the.copp.errwould;be reusedj with:

only sufiicient addition of'fresh' coppennitrateor' oxide to replace losses incident to handling. The

procedure would be to concentrate the filtratefrom the copper diisocinchomeronate:to.-a160%- nitric acid concentration and to add to this the copper oxide in moist form, precipitated during the regeneration of free isocinchomeroniaacid.

Example-2 In this example, generally the same oxidation conditions were followed and thesame quantities: of 5-ethyl-Z-methylpyridine, nitric acid and.

copper were used, a variation coming in .the fact that the excess nitric acid and copper from a previous. run were..used,,the copper. both from the concentrated acid' filtrate. and Y from the precipitated. copper. oxide. Afterv removal of'thematerials fromilie. reactor, the copper. diisocinchomeronate was; filtered and the wet salt'waswashed 1 free. from contaminants". While" still in moistforrm. thematerial was heated for one-half hourwitha 251% excess of'isodium' hydroxide; in theform of? a 7%.solution. The .separated copper" oxide. was filtered hot; and the cooled filtrate wasacidified with 6N 'I-IS'Oi .to a pH of "2.5'. The isocinchomeronic acidprecipitated' fromsolution andwas washed and'dried'. The over-all'yield of. this. acid' from the 5ethyl-2emethylpyridine amounted to 94.5%... The high" quality of the" product was shown by the factthattheneutral ization. equivalent was determined as 83153,

which valuechecks within limits ofexperi'mental error the. value .of. 83 .56 forpure'material.

Examplea 3 1 Copper nitrate inthenamount. of j 51') grams,,, as:

C11(NO3)213H2O, was mixedlwithfili grams of 60% nitric acid, and 25. grams.ofifi:ethyI Z methylpyri-- dine was added. Thewholewas.introducediinto.

net ratio of nitric acid to the pyridine. derivative. by-weight-was-3fi, anda 100% excess. of copperv was used. The copper. Salton isocinchomeronic acid was separated :and. purified as inExample 1, and a yield of 93.2.%-.was obtained;.

Example- 4' Nitric acid of-60 strength and in.the..amount oi-9 "pounds was introduced. into aA-gallon stainless-steel reactor. In .a separatevessel', 1.51 pounds of 5-ethyl-Z-methylpyridinev was.-

the reactor was heated'and the second solution was then .fedin, anadditionallfilpoun'ds of60% nitric being used to'wash out the feed line, so that a totalof l9.5..pounds of acid was present; i. e., a net. ratio by weight of nitric. acid to 5"- ethyl-2.-methylpyridine of 7.8.

to the .acidin thereactor. Themixture was then kept. at atemperature of total-period of. around.2 hours, a" pressure of- 210 pounds per square inch dissolved in. another 9- pounds.oi.60.%..nitric..acid;. The acid in.

Copper oxide in an amount of 2 pounds had previouslybeen added about" 180 C. for" a' (gage)- beingmain tained by periodic venting. At the end of the reaction, the contents were removed from the reactor, and the copper diisocinchomeronate separated as before a yield of 82% being obtained.

The copper'sa'ltithus ohtainedwas digested with a"50% excess of sodium hydroxide-in the form of a solution, and the precipitated copper oxide was filtered off. The filtrate was acidified with sulfuric.. acid.to a pH value of 2.5, and the free isocinchomeronic acid was separated, washed and dried. The amount of free acid obtained was 72'4 gramsgcomprising a yield of 94%, based on thecopper'salfior an over-all yield of 77% from 5'-ethyl2=methylpyridine. The isocinchomeronic acid obtainedwas of excellent quality.

Example 5 time was 015 hour, atemperature' oi'180" C. being 1 maintained. A-yield of 70.7% of' the-zincsa'ltwas 1 obtained.

Example 6..

In accordance again with. the procedure of Example 1, a metal' salt of 5 isocinchom'eronicr'acid was prepared; but'with the use of. nickel nitrate, in an'excess of 350%. A yieldmfithenickel;salt of isoeinchomeroniczacid oit 73.6% resulted;

Example 7.

In accordance with the procedure oiExample 1', 3.0 grams 5 ethyl-2-methylpyridine was oxidized by means of10%'- nitric acid inla' net-ratio by? weight of nitric" acid to 5"'-ethyl'- 2-methylpyri dine of 671 in the presence of '15 grams-of" coppernitrate, Cu(N0s) 2-3H2O; The reaction time was- 2' hours; a-- temperature of180" C. being maintained. A yield of copper diisocinchomeronate" of'55i4% was-obtained; Whenthe' reaction time. was 3"li"ours; the yield ofcopper diisocinchomer onate =was='%:

Example 8.

In" accordanceewithzthe PI'OGBdiIIB'lOf? Example 1; 310 grams5-ethyl 2+methylpyridine was oxid- Example, 9'

In-accord'ance with theeprocedure' ofiElxample 1, 3.0 grams 5-ethy1 2.-methylpyridinewas: oxidized. by means of 40% nitric acid i in a net: ratio". by weight of-nitric' acid" to 5 '-ethyl--2-methylpyri.- dine oi6/1 in thepresence of 15 grams of; copper:

nitrate; Cu(NC3)2-3H2'OZ The reactionatime-wasr 1 hour; a temperature of C; being main. tained; A yield of copper diisocinchomeronate? of 86.1% was obtained;

The foregoing examples showthat high .yields' of a product having exceptional purity were obtained. The product of Example? 2. had :a neutral; equivalent of 83:53. (83:56? is. the:- theoretical) In general, neutral equivalents: ofiabout 83.;573165 obtained by'my' process; whereas; in: oxidations. by means ofconcentratednitric. acid; without, a

metal salt, in accordance with the prior art, neutral equivalents of 85-88 have been the rule.

In the process described in the foregoing examples, the starting material may be any 2,5 dialkylpyridine, desirably one with relatively few carbon atoms present in the substituent groups, for example 2,5-dimethylpyridine, 5-ethyl-2- methylpyridine, and the like. Preferably I use the latter compound because it is an organic compound which can readily be prepared synthetically.

In carrying out the oxidation reaction, nitric acid is used, and I find it important to employ an excess of such acid, for example a net nitric acid ratio of over 3 parts by weight of nitric acid to 1 part of 5-ethyl-2-methylpyridine. While the nitric acid ratio cited considers the nitric acid at 100% strength, actually it may be used at any desired practical dilution. I find 60% nitric acid satisfactory for use, but it may be considerably more dilute, if desired. The reaction will be carried out at an elevated temperature, and, in the preparation of isocinchomeronic acid from 5-ethyl-2-methylpyridine, the temperature should be above 140 C., and desirably considerably higher, above 160 C. for example. The reaction will be carried out in a closed vessel and under pressure. The evolution of nitrogen oxides will cause the build-up. of pressure and, if

desired, a pressure of nitrogen may be used. Maintenance of the pressure at a predetermined value will be found advisable, and I do not wish to be limited with respect to pressure conditions.

An essential feature of the process is the carrying out of the reaction in the presence of a metallic salt of an inorganic or lower aliphatic acid. While copper sulfate or similar metal sulfate, copper acetate, or other salts might be used, the logical salt for use will be a metal nitrate, inasmuch as nitric acid is a necessary reactant, and, by the use of nitrates, the presence of additional acid ions is avoided. The nitrate may be introduced into the reaction as such, but a con venient procedure is to add a metal oxide to the reaction mixture, which becomes converted to the nitrate in the presence of nitric acid. Preferably I employ copper nitrate or a copper compound convertible to the nitrate by means of nitric acid, as particularly satisfactory results appear to be obtained with this metal. Salts of other bivalent metals are applicable, however, for example zinc, nickel, and the like. Desirably a considerable excess of metal salt is used over that required to supply sufiicient metal ions to form the metal salt of the pyridinecarboxylic acid. The presence of copper or other metal during the oxidation reaction is advantageous to the process in that, by causing the immediate formation of the stable metal salt, which is insoluble in the nitric acid reaction medium, it inhibits any decarboxylation of the pyridinedicarboxylic acid which might occur. The formation of lay-product nicotinic acid, which, in the nitric acid medium, tends to yield the soluble nitrate of nicotinic acid, which is separated from the desired pyridinedicarboxylic acid only with difficulty, is thereby avoided, and higher yields of isocinchomeronic acid of a higher degree of purity are thus made possible.

Furthermore, when metal in adequate amounts is present, the 2,5-dialkylpyridine can be oxidized by dilute nitric acid because the decarboxylation of isocinchomeronic acid which occurs at lower dilutions in the absence of adequate amounts of metal cannot then take place, since the a-CELlbOXYl group, which is the more reactive group and the more subject to decarboxylation, is firmly combined with the metal to form the metal salt, insoluble in the nitric acid medium.

It has been proposed heretofore to use catalytic amounts of metals, such as copper, in the nitric acid oxidation of alkyl-substituted pyridines such as 2,5-dialkylpyridines, but such amounts would not result in complete, immediate conversion of all of the isocinchomeronic acid produced to the insoluble metal salt, thereby removing the acid at once from further reaction. I have found that more than 0.5 gram atom of copper is required in the reaction mixture to effect complete removal of the isocinchomeronic acid as it is formed. Under the conditions of my process, one equivalent of the bivalent metal such as copper, zinc, or nickel reacts with two moles of isocinchomeronic acid, as indicated by the following elemental analyses for the copper, zinc, and nickel salts given below:

Found Calc. Found Calc. Found Cale.

Percent C 42. 30 42. 47 39. 56 42. 50 35. 77 43. 00 Percent H l. 40 2.02 2. 18 2.05 2. 07 2.06 Percent N 7. 50 7.08 6.12 7. 20 5. 70 7.16 Percent Metal... 15. 28 16. 07 15. 33 16. 45 12. 14. 98

There is thus required one gram atom of metal for each two moles of isocinchomeronic acid produced. In practice, an excess of this amount of metal is required, and a considerable excess assures immediate formation of the metal salt. High yields of the deep-blue copper salt have been obtained with a 10% to 900% excess of cupric nitrate above that calculated to form (C7H4O4N)2Cu from the 5-ethyl-2-methylpyridine used.

The efiicacy of my process is considered to be dependent upon the lack of solubility in nitric acid of the metal salt formed in the nitric acid medium of my process. Copper diisocinchomeronate, for example, is recovered as large, deep-blue crystals which are easily filtered. The salt is essentially insoluble in the nitric acid medium and is less than 0.05 gram soluble in 100 grams of water at 25 C. Copper salts of other pyridinecarboxylic acids, on the other hand, are, for the most part, soluble in nitric acid solution. My process cannot be applied to the preparation of copper quinolinate, for example, because the copper salt of quinolinic acid produced in the nitric acid medium is soluble in the nitric acid and cannot be recovered as a solid product. Copper nicotinate and copper picolinate are also soluble in nitric acid.

The invention includes not only the oxidation of a 2,5-dialkylpyridine to a metal salt of isocinchomeronic acid but also the further stage of acumen? convertingfisaid metallsaltitdthe free carbexylic.

acid. In thisilatter step; thetmetal .salt. is? heated with an excess; of. alkali. preferably an alkali hydroxide, for example, sodium hydroxide. When theLcQppersalt has been .used, copper oxide precipitates out .at'this pointand-is readily; removed by'filtration. The sodium salt remains'dissolved the: filtrate. On. addition of sulfuric acid or other strong inorganic.acidfithereto. and acidification toa pH of 2.5, that=isto-the point at-which substantially all of .the carboxylic acid-is present inutheiorm of free acid'rather than in combination witheithensulfuric acid. or a metal ion, the

isocinchomeronic; acid precipitates and may be separatedlay-filtration. It. will. be seen that the useofi an. excess of. the.- inorganic salt of copper or other metal. entails: no loss, inasmuchas themetal; is almost completely: available for subse.--

quent use; in the process, either: dissolved. in the nitric acid filtrate, whichcanreadilybe concen.-

trated to the desired strength, or as precipitated oxide; whichcanbe added directly in the moist, washed state:

llheprocess of the present invention has a number of advantages that make it superior. to.

It uses as starting materialscompounds that are available and economically attractive; specifically -ethyl-2-methylpyridine.'

prior art methods.

and. nitric acid. Particularly important are the excellent yields cbtainedand fully as-significant I pound andia compound capable oi yielding. in the reactiommedium. ionssof. a: bivalent metal taken from the? group consistingof copper, zinc, and nickel, saidcompoun'd being present in an amount greater: than that necessary to provide 0.5 gram atom of metal. for each mole of 2,5-dialkylpyridine, thereby formingmetal diisocinchomeronate. 2.. A processior the preparation of a coppersalt of isocinchomeronic acid, which comprises heatingat-a' temperature above l i0 C. and. at superatmospheric pressure 5-ethyl-2-methylpyridine, nitric' acid of a. concentration between 10 and.60.%; and a compound capable of copper ions-inthe reaction: medium, said combeing present man-amount greater than that necessary to provide 05 for; each. moleof. 5-ethyl-2-methylpyridine, thereby forming copper diisocinchomeronate.

3; Aprocess as:claimed in.c1aim.2, in whicha" net nitric acid ratio is used higher than 3.0.

parts .by 'weightof nitric acid per part of 5-ethyl-- Z-methylpyridinee 4. A: process for the preparation of' isocinchomeronio acid, which comprises heating at'a temperature above C. and under superatmos pheric pressure" 5 ethyl-2-methylpyridine, nitric a'cid'or a concentration between 10 and 60%, and a compound capable of yielding copper ions in the reaction medium, said compound being present in an amount greater than that necessary to provide 0.5 gram atom of copper for each mole of'5-ethyl-Z-methylpyridine; separating the pre-- cipitated crystals of copperdiisocinchomeronate.

and heating the crystals in thepresence of excess alkali; separating-the precipitated copper oxide from the solution; acidifying the solution with an: inorganic acid to a pI-Iiof about 2.5; and separating the precipitated isocinchorneronic acid.

HENRY HENDERSON HERRING, JR.

References-Gitedin the file of this patent UNITED STATES PATENTS Number Name Date 2,371,691. Hawkinsonet al. Mar. 20, 1945 2,524,957 Burrows'et' a1 Oct. 10, 1950 yielding gram atomof metal. 

1. A PROCESS FOR THE PREPARATION OF METAL SALTS OF ISOCINCHOMERONIC ACID, WHICH COMPRISES HEATING AT A TEMPERATURE ABOVE 140* C. AND UNDER SUPERATMOSPHERIC PRESSURE A 2,5-DIALKYLPYRIDINE, NITRIC, ACID OF A CONCENTRATION BETWEEN 10 AND 60%, AND A COMPOUND CAPABLE OF YIELDING IN THE REACTION MEDIUM IONS OF A BIVALNET METAL TAKEN FROM THE GROUP CONSISTING OF COPPER, ZINC, AND NICKE, AND COMPOUND BEING PRESENT IN AN AMOUNT GREATER THAN THAT NECESSARY TO PROVIDE 0.5 GRAM ATOM OF METAL FOR EACH MOLE OF 2,5-DIALKYLPYRIDINE, THEREBY FORMING METAL DIISOCINCHOMERONATE. 